Weeks Of Atrial Fibrillation Research Articles

High-density and high coverage composite mapping of repetitive atrial activation patterns

BackgroundRepetitive atrial activation patterns (RAAPs) during atrial fibrillation (AF) may be associated with localized mechanisms that maintain AF. Current electro-anatomical mapping systems are unsuitable for analyzing RAAPs due to the trade-off between spatial coverage and electrode density in clinical catheters. This work proposes a technique to overcome this trade-off by constructing composite maps from spatially overlapping sequential recordings. MethodsHigh-density epicardial contact mapping was performed during open-chest surgery in goats (n=16, left and right atria) with 3 or 22 weeks of sustained AF (249-electrode array, electrode distance 2.4 mm). A dataset mimicking sequential recordings was generated by segmenting the grid into four spatially overlapping regions (each region 6.5 cm2, 48±10% overlap) without temporal overlap. RAAPs were detected in each region using recurrence plots of activation times. RAAPs in two different regions were joined in case of RAAP cross-recurrence between overlapping electrodes. We quantified the reconstruction success rate and quality of the composite maps. ResultsOf 1021 RAAPs found in the full mapping array (32±13 per recording), 328 spatiotemporally stable RAAPs were analyzed. 247 composite maps were generated (75% success) with a quality of 0.86±0.21 (Pearson correlation). Success was significantly affected by the RAAP area. Quality was weakly correlated with the number of repetitions of RAAPs (r=0.13, p<0.05) and not affected by the atrial side (left or right) or AF duration (3 or 22 weeks of AF). ConclusionsConstructing composite maps by combining spatially overlapping sequential recordings is feasible. Interpretation of these maps can play a central role in ablation planning.

Atrial fibrillation and age synergistically increase clotting potential and promote atrial structural remodeling in goats

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Netherlands Heart Foundation, European Union Background Age is a risk factor for atrial fibrillation (AF) as well as for stroke in patients with AF. However, the effect of ageing on AF mechanisms and on coagulation activity is not well understood. Purpose To evaluate the effect of age and AF on coagulation activity, AF characteristics, and atrial structural remodeling. Methods Four groups of female goats were investigated: Young sham (Y-Sh: sinus rhythm, &amp;lt;3 years old, n=9), Young AF (Y-AF: 4 weeks of AF, &amp;lt;3 years old, n=7), Old sham (O-Sh: sinus rhythm, &amp;gt;8 years old, n=6), and Old AF (O-AF, 4 weeks of AF, &amp;gt;8 years old, n=8). Groups were matched for body weight. AF was maintained using implantable pacemakers in both AF groups. Clotting potential, expressed as the ability of activated plasma to generate thrombin, was measured using tissue factor-induced thrombin generation assays at baseline and 4 weeks (final). A terminal experiment was performed with atrial contact mapping to study electrophysiological AF properties and to collect atrial tissue for histological analysis. Results Thrombin generation analysis showed that 4 weeks of AF induced a significant increase in clotting potential in old, but not in young goats. AF complexity and hemodynamics were not affected by age alone. AF, however, significantly increased the right atrial pressure in old (O-Sh: 6.4±1.9 vs. O-AF: 11.4±3.1 mmHg, p=0.02), but not in young goats. AF induced atrial myocyte hypertrophy and left atrial epicardial endomysial fibrosis in old goats, while this was not the case in young goats. Conclusion Four weeks of AF and advanced age synergistically enhanced coagulation potential and promoted atrial structural remodeling in goats. Complexity of atrial conduction was affected by AF, but not by age.

B-PO01-019 COAGULATION POTENTIAL, ELECTROPHYSIOLOGICAL CHARACTERISTICS AND STRUCTURAL REMODELING DUE TO ATRIAL FIBRILLATION IN YOUNG AND AGED GOATS

Age is a risk factor for atrial fibrillation (AF) as well as for stroke in patients with AF. The effect of ageing on AF mechanisms and on coagulation activity is not well understood. To evaluate the effect of age and AF on coagulation activity, AF characteristics, and structural remodeling. Four groups of goats were investigated: Young sham (Y-Sh: sinus rhythm, <3 years old, n=9), Young AF (Y-AF: 4 weeks of AF, <3 years old, n=7), Old sham (O-Sh: sinus rhythm, >8 years old, n=6), and Old AF (O-AF, 4 weeks of AF, >8 years old, n=8). Groups were matched for body weight. AF was maintained using implantable pacemakers in both AF groups. Clotting potential was measured using tissue factor-induced thrombin generation (TG) assays at baseline and 4 weeks (final). A terminal experiment was performed with atrial contact mapping to study electrophysiological AF characteristics and to collect atrial tissue for histological analysis. The clotting potential, expressed as the ability of activated plasma to generate thrombin, did not differ among groups. However, AF in old goats caused an increase in coagulation potential (thrombin nM) while this was not the case in young goats. Complexity of fibrillatory conduction (no. of waves) was higher in AF groups after 4 weeks as compared to Sham, but there was no effect of age. AF-related atrial myocyte hypertrophy occurred in old but not in young goats. Endomysial fibrosis was similar in all groups. Four weeks of AF caused an increase in clotting potential and myocyte size in old but not in young goats. Age did not cause fibrosis or increased AF complexity.

Electrophysiological effects of ranolazine in a goat model of lone atrial fibrillation

There is still an unmet need for pharmacologic treatment of atrial fibrillation (AF) with few effects on ventricular electrophysiology. Ranolazine is an antiarrhythmic drug reported to have strong atrial selectivity. The purpose of this study was to investigate the electrophysiological effects of ranolazine in atria with AF-induced electrical remodeling in a model of lone AF in awake goats. Electrode patches were implanted on the atrial epicardium of 8 Dutch milk goats. Experiments were performed at baseline and after 2 and 14 days of electrically maintained AF. Several electrophysiological parameters and AF episode duration were measured during infusion of vehicle and different doses of ranolazine (target plasma levels 4, 8, and 16 μM, respectively). The highest dose of ranolazine significantly prolonged atrial effective refractory period and decreased atrial conduction velocity at baseline and after 2 days of AF. After 2 weeks of AF, ranolazine prolonged the p5 and p50 of AF cycle length distribution in a dose-dependent manner but was not effective in restoring sinus rhythm. No adverse ventricular arrhythmic events (eg, premature ventricular beats or signs of hemodynamic instability) were observed during infusion of ranolazine at any point in the study. The lowest investigated dose of ranolazine, which is expected to block both late INa and atrial peak INa, had no effect on the investigated electrophysiological parameters. The highest dose affected both atrial and ventricular electrophysiological parameters at different stages of AF-induced remodeling but was not efficacious in cardioverting AF to sinus rhythm in a goat model of lone AF.

The impact of 6 weeks of atrial fibrillation on left atrial and ventricular structure and function

ObjectiveThe impact of prolonged episodes of atrial fibrillation on atrial and ventricular function has been incompletely characterized. The purpose of this study was to investigate the influence of atrial fibrillation on left atrial and ventricular function in a rapid paced porcine model of atrial fibrillation. MethodsA control group of pigs (group 1, n = 8) underwent left atrial and left ventricular conductance catheter studies and fibrosis analysis. A second group (group 2, n = 8) received a baseline cardiac magnetic resonance imaging to characterize left atrial and left ventricular function. The atria were rapidly paced into atrial fibrillation for 6 weeks followed by cardioversion and cardiac magnetic resonance imaging. ResultsAfter 6 weeks of atrial fibrillation, left atrial contractility defined by atrial end-systolic pressure-volume relationship slope was significantly lower in group 2 than in group 1 (1.1 ± 0.5 vs 1.7 ± 1.0; P = .041), whereas compliance from the end-diastolic pressure-volume relationship was unchanged (1.5 ± 0.9 vs 1.6 ± 1.3; P = .733). Compared with baseline, atrial fibrillation resulted in a significantly higher contribution of left atrial reservoir volume to stroke volume (32% vs 17%; P = .005) and lower left atrial booster pump volume contribution to stroke volume (19% vs 28%; P = .029). Atrial fibrillation also significantly increased maximum left atrial volume (206 ± 41 mL vs 90 ± 21 mL; P < .001). Left atrial fibrosis in group 2 was significantly higher than in group 1. Atrial fibrillation decreased left ventricular ejection fraction (29% ± 9% vs 58 ± 8%; P < .001), but left ventricular stroke volume was unchanged. ConclusionsIn a chronic model of atrial fibrillation, the left atrium demonstrated significant structural remodeling and decreased contractility. These data suggest that early intervention in patients with persistent atrial fibrillation might mitigate against adverse atrial and ventricular structural remodeling.

Structural and Functional Alteration of RyR Clusters After Remodeling in Persistent Atrial Fibrillation

In chronic atrial fibrillation (AF), abnormalities in Ca2+ release from RyR have been implicated as major factors contributing to arrhythmia and contractile dysfunction, but the relation to RyR organization remains unknown. Using STED microscopy we examined RyR cluster morphology in isolated atrial myocytes from sheep with persistent AF (N=6, 16-23 weeks of AF) and age matched control (Ctrl) animals; in parallel experiments we measured Ca2+ sparks in permeabilized myocytes. STED measurements revealed RyR clusters typically contained 15 contiguous RyR and on average this did not differ between AF and Ctrl. However, the nearest neighbor distance between clusters was reduced in AF. Grouping of clusters within 150 nm as functional Ca2+ release units (CRU) indicated that in AF these units exhibit increased fragmentation, with more clusters per functional unit. Measurement of Ca2+ sparks in permeabilized myocytes revealed a >50% increase in spark frequency and a higher prevalence of macrosparks. Spark time-to-peak (TTP) and duration were also increased, but width was reduced. Measurement of the intrinsic cellular buffer capacity showed this was reduced in AF. Using computational modeling it was found that the increased TTP and duration can be ascribed to the increased number of clusters per functional grouping in AF. The observed increased CRU fragmentation and reduction in Ca2+ buffering, can increased occurrence of sparks and macrosparks in AF. In conclusion, ultrastructural reorganization of RyR clusters within the functional units contributes to overactive Ca2+ release with increased chance of propagating events in AF.

Long-Term Frequency Gradients During Persistent Atrial Fibrillation in Sheep Are Associated With Stable Sources in the Left Atrium

Dominant frequencies (DFs) of activation are higher in the atria of patients with persistent than paroxysmal atrial fibrillation (AF), and left atrial (LA)-to-right atrial (RA) DF gradients have been identified in both. However, whether such gradients are maintained as long-term persistent AF is established remains unexplored. We aimed at determining in vivo the time course in atrial DF values from paroxysmal to persistent AF in sheep and testing the hypothesis that an LA-to-RA DF difference is associated with LA drivers in persistent AF. AF was induced using RA tachypacing (n=8). Electrograms were obtained weekly from an RA lead and an implantable loop recorder implanted near the LA. DFs were determined for 5-second-long electrograms (QRST subtracted) during AF in vivo and in ex vivo optical mapping. Underlying structural changes were compared with weight-matched controls (n=4). After the first AF episode, DF increased gradually during a 2-week period (7±0.21 to 9.92±0.31 Hz; n=6; P<0.05). During 9 to 24 weeks of AF, the DF values on the implantable loop recorder were higher than the RA (10.6±0.08 versus 9.3±0.1 Hz, respectively; n=7; P<0.0001). Subsequent optical mapping confirmed a DF gradient from posterior LA-to-RA (9.1±1.0 to 6.9±0.9 Hz; P<0.05) and demonstrated patterns of activation compatible with drifting rotors in the posterior LA. Persistent AF sheep showed significant enlargement of the posterior LA compared with controls. In the sheep, transition from paroxysmal to persistent AF shows continuous LA-to-RA DF gradients in vivo together with enlargement of the posterior LA, which harbors the highest frequency domains and patterns of activation compatible with drifting rotors.

Epicardial Adipose Tissue and Neural Mechanisms of Atrial Fibrillation

In this issue of Circulation: Arrhythmia and Electrophysiology , Nagashima et al1 reported that there is higher epicardial adipose tissue (EAT) volume and greater serum inflammatory biomarker levels in patients with persistent atrial fibrillation (PerAF) than in patients with paroxysmal atrial fibrillation (PAF). Furthermore, they noted that high dominant frequency (DF) sites are located adjacent to EAT sites. The authors proposed 2 possible explanations for these findings. One is that EAT secretes proinflammatory cytokines that alter local atrial and pulmonary vein (PV) electrophysiology and facilitates the development of atrial fibrillation (AF). The second is that EAT contains abundant ganglionated plexi. Activation of the autonomic nerves in the ganglionated plexi facilitates the maintenance of AF. The results of the present study extended their previous observation on EAT2 by providing new data on the correlation between high DF sites and EAT sites. These novel observations provide new insights into the anatomic and physiological differences between PAF and PerAF. Article see p 676 After the initial diagnosis of PAF, there is a slow (5%–10% per year) but steady progression to chronic (permanent or persistent) AF.3 Baseline echocardiographic variables, age, cardiomyopathy, and heart rate are independently associated with progression to chronic AF. On the other hand, PerAF is also frequently the initial diagnosis without preceding PAF episodes. How often PerAF and permanent forms of AF are preceded by recurrent PAF remains unclear. Improving the understanding of PAF to PerAF progression may help secondary prevention efforts to reduce the complications associated with AF. Wijffels et al4 performed intermittent rapid atrial pacing in goats to study the progression of PAF to PerAF. They found that when AF is maintained artificially, the duration of the paroxysms progressively increases, becoming sustained after 1 to 3 weeks of AF. The transition from PAF to PerAF …

Atrial Sources of Reactive Oxygen Species Vary With the Duration and Substrate of Atrial Fibrillation

Background— An altered nitric oxide–redox balance has been implicated in the pathogenesis of atrial fibrillation (AF). Statins inhibit NOX2-NADPH oxidases and prevent postoperative AF but are less effective in AF secondary prevention; the mechanisms underlying these findings are poorly understood. Methods and Results— By using goat models of pacing-induced AF or of atrial structural remodeling secondary to atrioventricular block and right atrial samples from 130 patients undergoing cardiac surgery, we found that the mechanisms responsible for the NO-redox imbalance differ between atria and with the duration and substrate of AF. Rac1 and NADPH oxidase activity and the protein level of NOX2 and p22phox were significantly increased in the left atrium of goats after 2 weeks of AF and in patients who developed postoperative AF in the absence of differences in leukocytes infiltration. Conversely, in the presence of longstanding AF or atrioventricular block, uncoupled nitric oxide synthase activity (secondary to reduced BH 4 content and/or increased arginase activity) and mitochondrial oxidases accounted for the biatrial increase in reactive oxygen species. Atorvastatin caused a mevalonate-reversible inhibition of Rac1 and NOX2-NADPH oxidase activity in right atrial samples from patients who developed postoperative AF, but it did not affect reactive oxygen species, nitric oxide synthase uncoupling, or BH 4 in patients with permanent AF. Conclusions— Upregulation of atrial NADPH oxidases is an early but transient event in the natural history of AF. Changes in the sources of reactive oxygen species with atrial remodeling may explain why statins are effective in the primary prevention of AF but not in its management.

Re‐expression of alpha skeletal actin as a marker for dedifferentiation in cardiac pathologies

Differentiation of foetal cardiomyocytes is accompanied by sequential actin isoform expression, i.e. down-regulation of the ‘embryonic’ alpha smooth muscle actin, followed by an up-regulation of alpha skeletal actin (αSKA) and a final predominant expression of alpha cardiac actin (αCA). Our objective was to detect whether re-expression of αSKA occurred during cardiomyocyte dedifferentiation, a phenomenon that has been observed in different pathologies characterized by myocardial dysfunction. Immunohistochemistry of αCA, αSKA and cardiotin was performed on left ventricle biopsies from human patients after coronary bypass surgery. Furthermore, actin isoform expression was investigated in left ventricle samples of rabbit hearts suffering from pressure- and volume-overload and in adult rabbit ventricular cardiomyocytes during dedifferentiation in vitro. Atrial goat samples up to 16 weeks of sustained atrial fibrillation (AF) were studied ultrastructurally and were immunostained for αCA and αSKA. Up-regulation of αSKA was observed in human ventricular cardiomyocytes showing down-regulation of αCA and cardiotin. A patchy re-expression pattern of αSKA was observed in rabbit left ventricular tissue subjected to pressure- and volume-overload. Dedifferentiating cardiomyocytes in vitro revealed a degradation of the contractile apparatus and local re-expression of αSKA. Comparable αSKA staining patterns were found in several areas of atrial goat tissue during 16 weeks of AF together with a progressive glycogen accumulation at the same time intervals. The expression of αSKA in adult dedifferentiating cardiomyocytes, in combination with PAS-positive glycogen and decreased cardiotin expression, offers an additional tool in the evaluation of myocardial dysfunction and indicates major changes in the contractile properties of these cells.

P4-17: Conduction in the atrial free walls after short and long term atrial fibrillation in the goat

We have studied activation patterns during pacing and atrial fibrillation (AF) in goats after short term (2.5 weeks) and long term (6 months) AF. After 2.5 weeks of AF, electrical remodeling is complete. After 6 months of AF, structural remodeling has also become pronounced. At this time point, chemical cardioversion was no longer possible (permanent AF). We have evaluated whether the increased stability of AF is related to changes in conduction properties of the atrial free walls (AFWs).

Inhibitory G Protein Overexpression Provides Physiologically Relevant Heart Rate Control in Persistent Atrial Fibrillation

The need for new treatment strategies for cardiac arrhythmias has motivated our continuing development of gene therapeutic options. Previously, we reported a decreased heart rate in an acute model of atrial fibrillation after atrioventricular nodal gene transfer. Here, we expand those observations to persistent atrial fibrillation and severe heart failure. After 3 weeks of atrial fibrillation, domestic swine received atrioventricular nodal gene transfer with adenoviruses encoding beta-galactosidase (beta-gal), wild-type Galpha(i2) (wtGi), or constitutively active mutant (cGi). Heart rates in awake, alert animals were not altered by beta-gal or wtGi. cGi caused a sustained 15% to 25% decrease in heart rate. The wtGi effect became evident with sedation. A tachycardia-induced cardiomyopathy was present before gene transfer. In the beta-gal group, cardiomyopathy worsened over time. In the wtGi group, the condition improved slightly, and in the cGi group, ejection fraction was near normal at the end of the study. TUNEL staining results corroborated this finding. cGi overexpression in the porcine atrioventricular node causes physiologically relevant heart rate control in persistent atrial fibrillation. These data advance the development of gene therapy as a potential treatment for common cardiac arrhythmias.

Analysis of altered gene expression during sustained atrial fibrillation in the goat.

Atrial fibrillation (AF) is characterised by electrical, gap junctional and structural remodelling. However, the underlying molecular mechanisms of these phenomena are largely unknown. To get more insight into atrial remodelling at the molecular level we have analysed changes in gene expression during sustained AF in the goat. The differential display technique (DD) was used to identify genes differentially expressed during sustained AF (13.9 +/- 5.2 weeks) as compared to sinus rhythm (SR). Dot-blot analysis was performed to confirm the altered gene expression and to establish the changes in expression after 1, 2, 4, 8 and 16 weeks of AF. Immunohistochemistry and western blotting were used to validate the DD approach and to further characterise the changed expression of the beta-myosin heavy chain gene at the protein level. Of the approximately 125 fragments that showed changed expression levels during AF, 34 were cloned and sequenced. Twenty-one of these represented known genes involved in cardiomyocyte structure, metabolism, expression regulation, or differentiation status. The changed expression of 70% of the isolated clones could be confirmed by dot-blot analysis. In addition, time course analysis revealed different profiles of expression as well as transient re-expression of genes, e.g. the gene for hypoxia-inducible factor 1 alpha during the first week of AF. During sustained AF the frequency of cardiomyocytes expressing beta myosin heavy chain (beta MHC) increased from 21.8 +/- 2.1 to 47.9 +/- 2.5% (S.E.M.). The overall expression of MHC (alpha+beta) appeared to be down-regulated during AF. AF is accompanied by changes in expression of proteins involved in cellular structure, metabolism, gene expression regulation and (de-)differentiation. Most alterations in expression confirm or support the hypothesis of cardiomyocyte de-differentiation. Furthermore, the results suggest a role for ischemic stress in the early response of cardiomyocytes to AF, possibly via activation of hypoxia-inducible factor 1 alpha.

Increased myocardial GRP94 amounts during sustained atrial fibrillation: a protective response?

Structural and phenotypic changes of cardiomyocytes characterize atrial fibrillation. We investigated whether changes in the glucose-regulated protein GRP94, which is essential for cell viability, occur in the presence of chronic atrial fibrillation. Samples of fibrillating atrial myocardium obtained from both goat and human hearts were analyzed for GRP94 expression by an immunologic approach. In goats, atrial fibrillation was induced and maintained for 2, 4, 8, and 16 weeks. After 16 weeks of atrial fibrillation, cardioversion was applied and followed by 8 weeks of sinus rhythm. GRP94 levels doubled in goat atrial myocytes after 4 to 16 weeks of fibrillation with respect to normal atria and returned to control levels in atrial myocardium of cardioverted goats. Immunohistochemical analyses confirm that GRP94 increase occurred within cardiomyocytes. Significantly, increased levels of GRP94 were also observed in samples from human fibrillating atria. In the absence of signs of myocyte irreversible damage, the GRP94 increase in fibrillating atria is comparable to GRP94 levels observed in perinatal goat myocardium. However, calreticulin, another endoplasmic reticulum protein highly expressed in perinatal hearts, does not increase in fibrillating atria, whereas inducible HSP70, a cytoplasm stress protein that is expressed in perinatal goat hearts at levels comparable to those observed in the adult heart, shows a significant increase in chronic fibrillating atria. Our data demonstrate a large, reversible increase in GRP94 in fibrillating atrial myocytes, which may be related to the appearance of a protective phenotype.

Changes in Ultrastructural Calcium Distribution in Goat Atria During Atrial Fibrillation

It has been suggested that Ca2+content of atrial cardiomyocytes is increased at the onset of atrial fibrillation (AF). Whether this phenomenon is transient is currently unknown. Therefore, in this study the time-related changes in Ca2+location in atrial myocytes from goats with chronic AF have been investigated. The distribution of calcium was assessed with the electron microscope using the cytochemical phosphate-pyroantimonate and oxalate-pyroantimonate methods in atrial biopsies from goats in sinus rhythm and goats with 1–16 weeks of burst-pacing-induced AF. In atrial myocytes from control goats in sinus rhythm, a normal Ca2+distribution was observed, with regular deposits along the sarcolemma (an average of 3.4 deposits per μ m at a regular distance). The number of sarcolemma-bound Ca2+deposits substantially increased after 1 and 2 weeks of atrial fibrillation. After this period the amount of Ca2+precipitate decreased at 4 and 8 weeks, and became below control level at 16 weeks. A similar time-related redistribution of Ca2+occurred in mitochondria. Whereas mitochondria from control goats displayed very few Ca2+deposits (average 4.0 deposits per μ m2), their number markedly increased after 1 and 2 weeks of atrial fibrillation, which indicates cellular Ca2+overload. From 4 weeks, Ca2+deposits reached control levels and were below control level after 16 weeks of atrial fibrillation (2.5 deposits per μ m2). Our findings are consistent with the previously observed Ca2+overload early after the onset of atrial fibrillation. The present study shows that this overload persists for at least 2 weeks, after which the cardiomyocytes apparently adapt to a new Ca2+homeostasis, thereby avoiding Ca2+overload. This protection against Ca2+overload co-occurs with dedifferentiation like cellular remodeling.

Electrical remodeling due to atrial fibrillation in chronically instrumented conscious goats: roles of neurohumoral changes, ischemia, atrial stretch, and high rate of electrical activation.

Recently, we developed a goat model of chronic atrial fibrillation (AF). Due to AF, the atrial effective refractory period (AERP) shortened and its physiological rate adaptation inversed, whereas the rate and stability of AF increased. The goal of the present study was to evaluate the role of (1) the autonomic nervous system, (2) ischemia, (3) stretch, (4) atrial natriuretic factor (ANF), and (5) rapid atrial pacing in this process of electrical remodeling. Twenty-five goats were chronically instrumented with multiple epicardial atrial electrodes. Infusion of atropine (1.0 mg/kg; n=6) or propranolol (0.6 mg/kg; n=6) did not abolish the AF-induced shortening of AERP or interval (AFI). Blockade of K+(ATP) channels by glibenclamide (10 micromol/kg; n=6) slightly increased the AFI from 95+/-4 to 101+/-5 ms, but AFI remained considerably shorter than during acute AF (145 ms). Glibenclamide had no significant effect on AERP after electrical cardioversion of AF (69+/-14 versus 75+/-15 ms). Volume loading by 0.5 to 1.0 L of Hemaccel (n=12) did not shorten AERP. The median plasma level of ANF increased from 42 to 99 pg/mL after 1 to 4 weeks of AF (n=6), but ANF infusion (0.1 to 3.1 microg/min, n=4) did not shorten AERP. Rapid atrial pacing (24 to 48 hours; n=10) progressively shortened AERP from 134+/-10 to 105+/-6 ms and inversed its physiological rate adaptation. Electrical remodeling by AF is not mediated by changes in autonomic tone, ischemia, stretch, or ANF. The high rate of electrical activation itself provides the stimulus for the AF-induced changes in AERP.

Atrial Fibrillation Begets Atrial Fibrillation

In this study we tested the hypothesis that atrial fibrillation (AF) causes electrophysiological changes of the atrial myocardium which might explain the progressive nature of the arrhythmia. Twelve goats were chronically instrumented with multiple electrodes sutured to the epicardium of both atria. Two to 3 Weeks after implantation, the animals were connected to a fibrillation pacemaker which artificially maintained AF. Whereas during control episodes of AF were short lasting (6 +/- 3 seconds), artificial maintenance of AF resulted in a progressive increase in the duration of AF to become sustained (> 24 hours) after 7.1 +/- 4.8 days (10 of 11 goats). During the first 24 hours of AF the median fibrillation interval shortened from 145 +/- 18 to 108 +/- 8 ms and the inducibility of AF by a single premature stimulus increased from 24% to 76%. The atrial effective refractory period (AERP) shortened from 146 +/- 19 to 95 +/- 20 ms (-35%) (S1S1, 400 ms). At high pacing rates the shortening was less (-12%), pointing to a reversion of the normal adaptation of the AERP to heart rate. In 5 goats, after 2 to 4 weeks of AF, sinus rhythm was restored and all electrophysiological changes were found to be reversible within 1 week. Artificial maintenance of AF leads to a marked shortening of AERP, a reversion of its physiological rate adaptation, and an increase in rate, inducibility and stability of AF. All these changes were completely reversible within 1 week of sinus rhythm.